9alpha-hydroxy-11-oxygenated steroids and method of production



United States Patent 9u-HYDROXY-11-OXYGENATED STEROIDS AND METHOD OF PRODUCTION Robert P. Graher, Elizabeth, and Norman L. Weudler, Summit, N.J., assignors to Merck 8: C0,, Inc., Rahway, NJ., a corporation of New Jersey No Drawing. Filed Apr. 2, 1954, Ser. No. 420,734

14 Claims. (Cl. 260-39745) I l O B wherein R is a keto or hydroxy group. Apart tromhaving this essentialsystem in rings B and C, however, the novel 9a-hydroxy-l l-oxygenated pregnanes and pregnenes included within the scope of this invention may vary considerably in structure. Thus, the Qa-hydroxyll-oxygenated pregnanes and pregnenes may be substituted in one or more positions as follows, if desired: in the 3 position with a keto, hydroxy or acyloxy group; in the 17 position with an 1x or hydroxy group; in the 20 position with a keto group and in the 21 position with a hydroxy or acylated hydroxy group. In addition to such fully saturated pregnanes, similar pregnene compounds are also provided, as for example, pregnenes having double bonds :at one or more positions such as A A A A A and A If necessary, any such double bond may be intermediarily protected in known manner, for instance, by saturation with halogen or hydrogen halide or by conversion into pentacyclic isosteroids. Both the pregnanes and pregnenes as described above are made available in the normal and allo series when structurally possible according to the position of unsaturation.

Compounds having the structural criteria described above exert cortisone-like activity and adrenal hormone activity. They are also useful as intermediates in the preparation of other valuable steroid compounds.

The 9a-hydroxy-l1-oxygenated pregnanes and pregnenes of invention are conveniently produced according to unique processes starting with 95,11B-oxido derivatives of normal and allo pregnanes and pregnenes. By hydrolytically cleaving the 9/3,11floxide there is obtained the corresponding 9a,11fl-dihydroxy pregnane or pregnene. The 9a,ll,B-dihydroxy compound is then oxidized to the corresponding Qa-hYdI'OXY-l l-keto pregnane or pregnene.

Examples of 9 8,11B-oxides which may be used as starting materials are 918,1lfi-oxido-A' -pregnene-l7a,21-diol- 3,20 dione, 9fi,11p-oxidoA -pregnene-2l-ol-3,20-dione and 2l-acylates of such compounds, such as the acetate, propionate, butyrate, benzoate and phenylacetate, 9 6,115-

? pregnene-3,20-dione,

oxido-A -pregnene-l7u-ol-3,3 O-dione, 95,11 8 oxido A 95,11,8-oxido-M-pregnene 3 one, similar compounds having a 3oc-hYdl'OXY-l or 3B-hydroxyl group or acylates thereof such as previously specified, and the corresponding compounds in the pregnane and allopregnane series. In addition, pregnenes similar to those specified but having double bonds such as in the A A and A' positions rather than at A may also be used. These and related compounds are conveniently prepared by methods known in the art such as is de- 7 scribed in the J. Am. Chem. Soc., 75, 2273 (1953).

I from 24 to 72 hours.

pounds.

In the first step of this invention the 95,1118-oxido 9B,l1B-oxido pregnane or pregnene with the mineral acid in aqueous solvent mixture. It is preferred .that the organic solvent employed be nonreactive with the steroid compound. Solvents such as dioxane, tetrahydrofuran, acetone, benzene, diethyl ether andthe like are satis'. factory. The presence of Water is required in order to insure formation of the desired glycol. At room temperature the reaction proceeds slowly, often requiring By the use of slightly elevated temperatures the reaction time may be reduced considerably. After the the reaction has gone to completion the desired 9a,11fi-dihydroxy pregnane or pregnene can be conveniently recovered trom the reaction mixture by known methods. Thus, the reaction mixture may be extracted with a suitable solvent and the solvent extract washed with water to remove acid.' The organic layer is evaporated to dryness under reduced pressure to obtain the product.

One reaction illustrative of this method is the treatment of 9 3,1lfi-oxido-M-pregneue-l7a,21-diol-3,20-dione with perchloric .acid to produce A -pregnene-9a,11fl,' 17a,21-tetro13,20-dione. This reaction may also be applied to the corresponding 21-acylates of the starting material, such as 918,11B-oxido-A -pregnene-17oc,21-diol- 3,20-dione-21-acetate, but in the course of the reaction the 21-acyl' group may be hydrolyzed and the desired 9a,11[3-dihydroxy pregnane obtained as the 2laalcohol. Examples of other novel compounds that are produced in the described manner starting with either the 21-hydroxy pregnanes, or pregnenes, or ZI-acylates thereof, are A -pregnene-9u,11fi,21-triol-3,20-dione, M-pregnene 9a, l1fi,l7a-triol-3,20 dione, A -pregnene 9a,1l;8-diol-3,20-i dione, 'A -pregnene-9a,.1 l/3diol-3-one, pregnane-9o '1t113, 2'l-triol-3,20-dione, pregnane-311,901,115,17a, 21-pento1 20 one, pregnane-9nd1 3,17a-1triol3,2O-dione, pregnane-9oz, l=1fi-diol-3,20-dione, pregnane-3 a,9a, 1 LB-triol-ZO-one preg: nane-9a,1 lfladiol-3 -one, pregnane-3 a,9a,11[3,2A1-ietrO1-20- one, pregnane-3/8,9m,l15,21-tetrol-20-one, pregnane-3a,9a, 1 1/3,17ott6tl01200116, pregnane-3 6,90; 1 B, 17 a,tetrol 20- one, allopreguane9a,l1 3,l7a,21-tetrol-3,20 dione, allo-, pregnane-rd 15,21-.triol3,20-dione, allopregnane-9a,11fi, l 7a,21-tetrol-20-one, :allopregnane-9a,1 lp,Q.1-trio1-20-one, allopregn-ane-9a,1 lfl,17a-triol-3,20 dione, 'allopregnane- 9a,l:1/3-.diol-3,20-dione, allopregnane-3a,9a,l113,21-tetro1- 2'0-one and the like. i

These'and similar compounds having hydroxy groups in the 3 and/or 21 positions may be reacted with .an acylating agent to obtain the corresponding acylated com- This reaction is conveniently efiected by treating the 3 and/ or 21 hydroxy compounds with acylating agents such as carboxylic acid anhydride, halide, ester or ketone under solvent conditions. An excess of liquid acylating agent such as the lower carboxylic acid anhydrides, or a suitable inert organic solvent such as Patented Sept. 13, 1960 pyridine and alkyl derivatives thereof, tertiary bases such as dialkyl anilines, quinolines and trialkyl amines may be utilized as the solvent medium. The reaction proce'e'ds at'rooni temperature and is, complete introm' about 1 to 1-2 hours. After the reaction is complete the mixture may be -diluted'with water to decompose the excess acyla'ting agent. 'The product may be recovered by extraction of, the aqueous mixture with an immiscible solvent sucli'asv ethyl acetate followed ,by evaporation of the organic extract to dryness. In this manner, mono and/or diacylates such as the acetate, propionate, butyrate,

benzoate and phenylacetate of the 90:,1113-dihYd1'0XY compounds such as those listed above may be produced.

The 9a,l1;3.-dihydroxy compounds are. conveniently converted'to the corresponding 9a-hydroxy-11-keto compounds by the action of an oxidizing agent. Any suitable oxidizing agent may be employed but is usually preferred to employ chromium trioxide in glacial acetic acid or an' N haloaniide or imide such as N-bromoacetamide in an inert solvent. The reaction goes to completion in a reasonably short time at room temperature, e.g., 10 minutesusually being adequate when chromium trioxide is employed and somewhat longer times being preferred with otheroxidizing agents. The desired product maybe readily recovered from the reaction mixture by standard isolation techniques.

I In general, any ofthe 9a,l15-dihydroxy pregnanes,

dioxane and 36 ml. of 2.0 M, aqueous perchloric acid was allowed to stand at room temperature for 65 hours. The solution became deep yellow in color. About 185 ml. of saturated aqueous sodium chloride was added and two layers separated. To the mixture was added 100 ml. of ethyl acetate followed by shaking. The layers were separated and the aqueous layer was extracted three times with 50ml; portions of ethyl acetate. The combined organic extracts were washed with water, saturated salt solution'and'filtered. 'By evaporating the orgauic filtrate to dryness there was obtained 'a yellow crystalline residue "of?A4-pregnene-9a,11,8,17a,2l1tetro1- 3,20-dione. The product was recrystallized from acetonechloroform and then from acetone: M.P. 243-249 'C. (dec.); k max. in OH OH=2420 A.

" l7a,2l-tetrol-3,20-dione in 2.0 ml. of acetic anhydride allopregnanes and pregnenes'such as those disclosed here- Y inabove may beoxidized to the corresponding 9u-hydroxy-ll-k'etoj compounds. When other oxidizable substituents are present in other parts of the molecule, they are preferably deactivated or protected against oxidation, such as by esterification. Such'protective, groups, e.g., esters, are not hydrolyzed during the oxidation but, on the contrary, the desired 9u-hydroxy-11-keto compounds are obtainedas the corresponding esters. Although any suitable esters may be prepared and used, it is generally preferred to employ esters in which theacyl group is aliphatic and contains 1 to 8 carbon atoms.

A specific illustration of this oxidation reaction is the treatmeut'of A* -pregnene-9a,1113,170:,2l-tetrol-3,20-dione- ZI-acetate with chromium trioxide in glacial acetic acid containing a trace of water to produce A -pregnene-9a, 17d,21-triol-3,l1,20-trione-2l-acetate. Similarly, starting with other 2l-esters of A -pregnene-9a,115,17a-21-tetrol- 3,20-dione such as the propionate, butyrate, benzoate and the like, there is obtained the corresponding 2l-ester of A pregnene-9a,17u,'21-triol 3,11,20 trione. Other compounds which may be readily produced by oxidation of'the corresponding 9a,11 8-dihydroxy compounds are A -pregnene-9a,2l-diol-3,l1,20-trione-21-acetate, A -pregnene-9a,17m-diol-3,l1,20-trione, A pregnene-9u-ol-3,ll, 20 trione, A pregnene-9a-ol-3,1l-dione, pregnane-9a,21- diol-3,1 1,20-trione-2l-acetate, 'pregnane-9a, l7u -diol-3, l l, 20-trione-pregnane-9a-ol-3,11,20-trione, pregnane-9a-ol- 3,11-dione, pregnane 3m,9oz,21-tI'iO1-11,20-di0I16-3,21-diacetate, pregnane-3fi,9a,2l triol-l1,20 dione-3,21-diacetate, pregnane 3a,9a,l7a-triol-11,20-dione-3-propionate, pregnane-3B,9a,17a-triol 11,20 dione-S-hemisuccinate, allopregnane 9oz,17oz,21 triol-3,11,20-trione-2l-acetate, allopregnane-9m,21-diol-3,11,20-trione 21 acetate, allopregnane-9a,17a-dio1-3,l1,20-trione, allopregnane-9a-ol-3,

and 0.32 ml. of pyridinewas allowed to stand at room temperature overnight. The solvents were removed and the residue triturated with 3.0 'ml. of water. The colorless solid was filtered and washed with water and ether. On recrystallization from acetone-ether the M-pregnene- 911,11 3,l7a,21-tetrol-3,20-dione-2l-acetate melted at'214- 216.5" C.; A max. in CH OH=M20 A.

A -pregnene-9a,11fl,21-triol-3,20-di0ne (9oc-hydr0xyc0rticosterone) and the ZJ-acerate thereof About 0.550 g. of 95,1lp-oxido-A -pregnene-2l-ol-3,

" 20-dione-21-acetate was added to 10.7 ml. of dioxane.

' overnight at room temperature.

11,20-trione, allopregnane-3a,9a,2l-triol-l1,20-dione-3,21-

EXAMPLE 1 A' -preg nene-9|ir,11,Ei,1711,21-tetr0l-3,20-dione (9a-hydroxy- 'hydrocortisone) and the 21 -acetate thereof 9. A solution of 4.345 g. of 9,8,11,8-oxido-M-pregnene- '170:,2lrdiol-3,20rdione 2l-acetate in 72 ml. of rifi d Then 5.4 ml. of 2.0 M aqueous perchloric acid was added to the solution and the mixture was allowed to stand for 67 hours at room temperature. The resulting deep yellow solution was treated as in Example 1 to isolate A -preg nene-9a,l1fl,21-triol-3,20-dione; M.P. 217-2225 C. with previous softening. V

j A 250 mg. sampleof A -pregnene-9a,l1B,21 triol-3,20- dione was added to 3.5 ml. of acetic anhydride and 0.55 ml. of pyridine. The solution was allowed to stand About 20 ml. of water was added cautiously to the reaction mixture which was then extracted with ethyl acetate. The organic extracts werewashed with dilute hydrochloric acid, water, 5% aqueous sodium bicarbonate and water. The organic extract was evaporated to dryness to obtain A -pregnene- 9cz,llfl,2l-triol-3,20-dione-2l-acetate; M.P. l7ll75 C. after recrystallization from acetone-ether.

The 9 3,115 oxido A -pregnene-2l-ol-3,20-dione-2lacetate was prepared as follows: V

A solution of 0.740 g. of 9a-bromo-A -pregnene-11,21- diol-3,20dione-2l-acetate and 0.940 g. of potassium acetate in 34 ml. of absolute ethyl alcohol was-heated under reflux for one andone-half hours under nitrogen. The mixture was then evaporated to dryness. The crys talline residue was treated with 50 ml. of water and the organic material extracted with ethyl acetate. The ethyl acetate extracts werecombined and washed. By evaporating the solvent and recrystallization of the residue from acetone-ether 95,1lfi oxido-A -pregnener2led-3,20- dione-Zl-acetate was obtained, M.P. 137-140 .C.

7 EXAMPLE 3 A -p regn erz e-9m1 7e,21-tr iol-'3,1 1,20-triorte (Qa-hydroxy- I cortisone) and the ZI-Vacetaze thereof acetate extracts were washed four times with water, five times with 5% aqueous sodium bicarbonate, and twice with saturated salt solution. After drying, the ethyl acetate was removed in vacuo to give a colorless crystalline residue, weight 358 mg. M.P. 228.5-235 C. with previous softening. Two recrystallizations from acetoneether afforded A -pregnene-Sm,17m,21-triol-3,11,20-trione- 21-acetate as rosettes of needles: M.P. 237-2435 C.; A max. in CH OH=2380 A.

Analysis.-Calcd. for C H O C. 66.01; H, 7.23. Found (dried at 100): C, 66.14; H, 7.02.

A suspension of 418.5 mg. of A -pregnene-9a,17a,21- triol-3,11,20-t1ione-21-acetate in 11 ml. of methanol is heated to reflux in a nitrogen atmosphere. Then 2 ml. of 1.0 M aqueous potassium bicarbonate was added to the refluxing solution. After minutes the reaction mixture is cooled to room temperature and the excess potassium bicarbonate was neutralized with dilute acetic acid. The solvents were removed by evaporation, the residue was taken up in 10 ml. of water and the aqueous mixture was extracted with ethyl acetate. The A regnene-Qu,l7a,2l-triol-3,11,20-trione was isolated by evaporation of the ethyl acetate.

EXAMPLE 4 A -pregnene-9a,21dial-3,11,ZO-trione (9a-hydr0xy-11-dehydracorticosterone) and the ZI-acetate thereof To a solution of 32.7 mg. of chromium trioxide in one drop of water and 1.5 ml. of glacial acetic acid was added 194 mg. of A -pregnene-9a,1lB,21-triol-3,2O-dione-21- acetate. The solid dissolved readily on stirring. After standing 10 minutes at room temperature the mixture was diluted with 8.5 ml. of water. The fine needles of A pregnene-9a,21-dio1-3,l1,20-trione-21-acetate which separated were filtered, washed with Water and dried; M.P. 230.5-236 C. after recrystallization from acetone-ether; A max. in CH OH=2380 A.

Saponification of the 2l-acetate to give A -pregnene- 9u,17a,21-triol-3,11,20-trione was efiected as in Example 3.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

What is claimed is:

l. A compound selected from the group consisting of A -pregnene-9a,l1,8,17a,2l-tetrol-3,20-dione, A -pregnene- 9a,17ct,211I-i01 3,11,20 trione, A -pregnene-9a,1 15,21- triol-3,20-dione, A -pregnene-9a,21-diol-3,1 1,20-trione and 21-acyloxy derivatives thereof wherein the acyl radical is derived from an organic carboxylic acid having less than nine carbon atoms.

2. A -pregnene-9a,11 6,17u,21-tetrol-3,20-dione.

3 A -pregnene-9u, 1 l5,21-triol-3,20-dione.

4. A -pregnene-9a,l7a,2l-trio1-3,11,20-trione.

5. The process which comprises reacting a 95,115- oxido-20-keto-steroid having the pregnane carbon skeleton with an aqueous strong rnineral acid to produce a 941,11 dihydroxy-ZO-keto steroid having the pregnane structure, deactivating oxidizable groups except the ,1lfi-dihY- droxy groups and reacting said compound with an oxidizing agent to produce the corresponding 9a-hydroxy-11,20- diketo steroid.

6. The process which comprises reacting a 95,1118- oxido-ZO-keto-steroid having the pregnane carbon skeleton with an aqueous strong mineral acid to produce a 9a,11;9- dihydroxy-ZO-keto steroid having the pregnane structure.

7. The process which comprises reacting a 95,115- oxido-M-pregnene-Zl-ol-20-one with an aqueous strong mineral acid to produce a A -pregnene-9a,l1p,2l-triol- 20-one.

8. The process which comprises reacting a 9,8,11,6- oxido-A -pregnene-17u,2l-diol-3,20-dione with an aqueous strong mineral acid to produce a A -pregnene-9a,11p,l7a, 2l-tetrol-3,20-dione.

9. The process which comprises reacting a 95,11,6- oxido-A -pregnene-21-ol-3,20-dione with an aqueous strong mineral acid to produce a A -pregnene-9a,1l,9,21- triol-3,20-dione.

10. The process which comprises reacting a 90:,115- dihydroxy-ZO-keto-steroid having the pregnane carbon skeleton with an oxidizing agent to produce the corresponding 9a-hydroxy-11,20-diketo steroid.

11. The process which comprises reacting a A -pregheme-9a,11 3,17oz,21-tetrol-3,20-di0ne 21-acylate wherein the acyl radical is derived from an organic carboxylic acid having less than nine carbon atoms with an oxidizing agent to produce the corresponding A -pregnene-9a,l7a, 21-triol-3,1 1,20-t1ione-21-acylate.

12. The process which comprises reacting a A -pregnene-9u,11fi,2l-triol-3,20-dione 21-acylate wherein the acyl radical is derived irom an organic carboxylic acid having less than nine carbon atoms with an oxidizing agent to produce the corresponding A -pregnene-9a,21- diol-3,1'1,20-trione-21-acylate.

13. A -pregnene-9a,1l;9,17a,21-tetrol 3,20 dione-Zlacetate.

14. A -pregnene 9a,l7a,21 triol-3,l1,20-trione-21- acetate.

References Cited in the file of this patent UNITED STATES PATENTS Laubach May 28, 1957 OTHER REFERENCES 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF $4-PREGNENE-9A,11B,17A,21-TETROL-3,20-DIONE, $4-PREGNENE9A,17A,21-TRIOL - 3,11,20 - TRIONE, $4-PREGNENE-9A,11B,21TRIOL-3,20-DIONE, $4-PREGNENE-9A,21-DIOL-3,11,20-TRIONE AND 21-ACYLOXY DERIVATIVES THEREOF WHEREIN THE ACYL RADICAL IS DERIVED FROM AN ORGANIC CARBOXYLIC ACID HAVING LESS THAN NINE CARBON ATOMS. 